Frequent p53 mutations and occasional loss of chromosome 4 in invasive bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in B6D2F1 mice.
B6D2F1 mice (45/group) were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or uracil as follows: Group 1 received 0.05% BBN in drinking water for the entire experiment, Group 2 received 5 mg of BBN by gastric gavage in 0.1 mL of 20% ethanol twice per week for 10 wk, Group 3 received a 2.5% uracil-containing diet for the entire experiment, and Group 4 was controls (received 0.1 ml of 20% ethanol by gavage twice per week for 10 wk). The surviving mice in Group 1 were killed after week 26 and those in the other groups after week 30. By week 15, three of 11 Group 1 and one of 15 Group 2 mice had bladder carcinoma. By 26 and 30 wk, respectively, invasive carcinomas were observed in 33 of 34 and six of 21 mice in Groups 1 and 2 and renal pelvic carcinomas in 11 of 34 and three of 21 mice in Groups 1 and 2. Four of 19 uracil-treated mice had bladder nodular hyperplasia. By polymerase chain reaction-single-strand conformation polymorphism and sequence analyses, 16 of 20 and two of five bladder carcinomas from Groups 1 and 2, respectively, showed mutations in the p53 gene. Ha-ras mutation was present in one case. Loss of heterozygosity analysis with simple-sequence length polymorphism markers for chromosome 4 showed that 10 of 21, two of 15, and nine of 13 mice in Groups 1-3, respectively, had heterozygous or homozygous deletions. B6D2F1 mice are therefore susceptible to the urothelial carcinogenic effects of BBN and develop frequent p53 mutations and chromosome 4 deletions. Chromosome 4 deletions were also seen with uracil.
Ogawa
K
K
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, USA.
Uzvolgyi
E
E
St John
M K
MK
de Oliveira
M L
ML
Arnold
L
L
Cohen
S M
SM
D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002872:Chromosome Deletion; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014498:Uracil / Q000008:administration & dosage / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D002085:Butylhydroxybutylnitrosamine; D014498:Uracil